1. Field of the Invention
This invention relates to novel antiestrogen compounds having effective antagonistic capability while-lacking agonistic effects. More particularly, certain preferred enbodiments of the invention relate to certain non steroidal diphenylethane or diphenylethylene analogs which have high affinity for estrogen receptors but do not activate such receptors.
2. Brief Description of the Prior Art
For the treatment of certain estrogen-dependent diseases, it is important to greatly reduce, or, if possible, eliminate estrogen-induced effects. Alternative or concurrent therapy to administration of antiestrogens could involve attempts to block the production of estrogens such that none is available to activate receptor sites. However, prior art methods for blocking estrogen production and/or reducing estrogen concentrations are not satisfactory and have only partial efficacy in inhibiting estrogen-induced functions. Moreover, it is possible that even in the total absence of estrogens, unoccupied estrogen receptors may be biologically active. See Simard and Labrie, "Keoxifene shows pure antiestrogenic activity in pituitary gonadotrophs": Mol. Cell. Endocrinol. 39: (1985) 141-144, especially page 144. Hence, antiestrogens may produce greater therapeutic results than therapy which only inhibits estrogen production.
Antiestrogens may have a significant therapeutic effect in slowing or stopping the progress of estrogen-dependent diseases, such as female breast cancer. Known antiestrogens have affinity for estrogen receptors and are at least moderately effective in blocking these receptors and preventing the formation of estrogen/receptor complex. Because this complex activates numerous estrogen-induced functions, blocking the formation of the complex substantially prevents or retards these estrogen-induced functions. However, prior art antiestrogens, while blocking the receptors, may themselves activate receptors, especially under in vivo conditions, and thus induce estrogenic effects. This "agonistic" activity of prior art antiestrogens can greatly diminish the therapeutic effectiveness of the antiestrogen.
There is, therefore, a need in the art for antiestrogens which effectively block estrogen receptors with minimal or no agonistic effect. Numerous compounds have been tried in the art with mixed results. Known antiestrogens continue to exhibit undesirable agonistic activity. See, for instance, Wakeling and Bowler, "Steroidal Pure Antioestrogens", J. Endocrinol. 112 (1987) R7-R10. The net effectiveness of prior art compounds is determined by the balance between their agonistic and antagonistic activities. Certain steroidal derivatives similar to those disclosed in the foregoing article, and which are stated to have antioestrogenic effect, are set forth in Bowler et al., U.S. Pat. No. 4, 659,516.
In U.S. Pat. No. 4,094,994, it is disclosed that the use of antiestrogens inhibit certain human breast tumor cells.
H. Mouridsen et al., Cancer Treatm. Rev. 5 (1978) 131-141, discloses that Tamoxifen, an antiestrogen, is effective in remission of advanced breast cancer in about 30 percent of the women patients treated.
The combined use of the antiestrogen Tamoxifen and a luteinizing hormone-releasing hormone agonist, Buserelin, is also known for treatment of breast cancer. See, for instance, Klijn et al. J. Steroid Biochem. 420 (no. 6B) (1984) 1381. The objective remission of such cancers, however, remains unacceptably low.
In U.S. Pat. No. 4,659,516, Bowler et al. report antiestrogenic activity for certain 7.alpha. substituted derivatives of estradiol.